The present invention relates to 3-demethoxyfortimicin A, 3demethoxyfortimicin B, 4-N-substituted derivatives of 3-demethoxyfortimicin B, and their pharmaceutically acceptable salts, to intermediates useful in the preparation of these compounds, and to compositions comprising these compounds and pharmaceutically acceptable carriers or diluents.
The fortimicins are a relatively new class of aminoglycoside antibiotics which are useful in the treatment of susceptible bacterial infections. Fermentation produced fortimicins include fortimicin A, disclosed in U.S. Pat. No. 3,976,768; fortimicin B, disclosed in U.S. Pat. No. 3,931,400; and fortimicin C, disclosed in U.S. Pat. Nos. 4,048,015 and 4,097,428. Other fermentation fortimicin factors have also been isolated.
Once an aminoglycoside antibiotic has been in clinical use for a period of time, resistant microorganisms may develop. In many cases, the resistance is R-factor mediated and is attributed to the ability of the bacteria to enzymatically modify the amino or hydroxyl groups of the aminoglycoside antibiotics and thereby reduce or eliminate their antibacterial properties. Thus, there is also a need for new entities which can be held in reserve to combat strains which have become resistant to treatment by the clinically used antibiotics. In the past, it has been found that the antibacterial and pharmacological properties of many naturally produced aminoglycoside antibiotics can be altered by structural modifications. As an example, certain chemical modifications in the gentamicin and kanamycin family of aminoglycoside antibiotics provide structures which are less toxic than the parent antibiotic. Further, in the same series, certain modifications alter the antibacterial spectrum advantageously either by increasing the intrinsic activity or increasing activity against resistant strains.
It has been previously determined that certain chemical modification of the parent fortimicins can also result in derivative compounds which exhibit increased antibacterial activity with respect to particular microorganisms, reduced toxicity, or equivalent of reduced activity, but nevertheless are useful as reserve antibiotics in the event resistant strains develop after a period of clinical use of one or more of the fortimicins. For example, 4-N-acyl and -alkyl derivatives of fortimicin B and techniques for forming these compounds are disclosed in U.S. Pat. Nos. 4,091,032; 4,155,902; 4,173,564; 4,174,312; 4,220,775 and 4,231,924; the disclosures of which are specifically incorporated herein by reference; and others. The fortimicin compounds have also been demethylated at the 3-position to provide useful derivatives. For example, 3-O-demethylfortimicins are disclosed in U.S. Pat. Nos. 4,124,756; 4,187,297; 4,220,756; 4,230,848; 4,242,503; 4,251,516 and 4,293,689.
While a number of fortimicin derivatives have been made to date, and valuable therapeutic agents have been identified, it is desirable to obtain new fortimicin antibiotics which exhibit a broader or different antibacterial spectrum, less toxicity, oral activity, or other desirable properties, or which can be held in reserve and used to treat infections caused by organisms which become resistant to other fortimicin therapy.
The present invention relates to novel 3-demethoxyfortimicins which exhibit antibacterial activity. More specifically, the present invention relates to 3-demethoxyfortimicin A, 3-demethoxyfortimicin B, and 4-N-substituted-3-demethoxyfortimicin B, to intermediates and processes useful in the production of these novel compounds, and to compositions comprising these compounds and a pharmaceutically acceptable carrier or diluent.